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Objectives: To describe swallowing and feeding-tube outcomes in patients with high-risk oropharyngeal cancer treated with trimodality therapy (TMT), including transoral robotic surgery (TORS) and adjuvant chemoradiotherapy., Methods: A chart review was conducted on patients with HPV+ OPSCC receiving TMT with TORS at an academic medical center from March 2010 to March 2021. Data collected included demographics, treatment, feeding tube placement, functional oral intake scale (FOIS) scores, and swallowing-language pathology (SLP) evaluations., Results: A total of 255 patients met selection criteria (mean age 61 years, 88% male). Following intraoperative nasogastric tube (NG) placement, 31% remained NG tube dependent after 3 weeks. A gastrostomy tube was placed in 19% of patients, and at 1 year after end-of-treatment (EOT), 3.5% overall remained tube-dependent. Mean FOIS scores were 6.9 (SD = 0.3) at pre-operative visit, 2.6 (1.8) at first post-operative visit, and 5.5 (1.5) after EOT. In the subset of patients with follow-up longer than 2 years (n = 118), the mean FOIS was 6.1 (SD = 1.3) at most recent visit. Clinical signs of aspiration/penetration were suspected on SLP evaluation in 18% of patients. These patients were subsequently evaluated with fiberoptic endoscopic evaluation of swallowing (FEES) and/or barium swallow study, which confirmed signs of aspiration in 2.7% of patients overall. Delayed NG tube removal after 3 weeks was predictive of (1) gastrostomy tube requirement and (2) clinical signs of aspiration on an SLP visit after EOT., Conclusions: Favorable functional and feeding-tube outcomes are demonstrated in patients with HPV-associated OPSCC undergoing TMT. In this single-institution study, we found low rates of long-term feeding tube dependence and high median FOIS following treatment. Review of routine SLP visits provides a detailed and easily accessible means for assessing swallowing function in this cohort., Level of Evidence: 4 Laryngoscope, 133:3013-3020, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To determine whether 2 different methods of post-operative head and neck free flap monitoring affect flap failure and complication rates., Methods: A retrospective chart review of 803 free flaps performed for head and neck reconstruction by the same microvascular surgeon between July 2013 and July 2020 at 2 separate hospitals within the same healthcare system. Four-hundred ten free flaps (51%) were performed at Hospital A, a medical center where flap checks were performed at frequent, scheduled intervals by in-house resident physicians and nurses; 393 free flaps (49%) were performed at Hospital B, a medical center where flap checks were performed regularly by nursing staff with resident physician evaluation as needed. Total free flap failure, partial free flap failure, and complications (consisting of wound infection, fistula, and reoperation within 1 month) were assessed., Results: There were no significant differences between Hospitals A and B when comparing rates of total free flap failure, partial free flap failure, complication, or re-operation ( P  = .27, P  = .66, P  = .65, P  = .29, respectively). There were no significant differences in urgent re-operation rates for flap compromise secondary to thrombosis and hematoma ( P  = .54)., Conclusions: In our series, free flap outcomes did not vary based on the degree of flap monitoring by resident physicians. This data supports the ability of a high-volume, well-trained, nursing-led flap monitoring program to detect flap compromise in an efficient fashion while limiting resident physician obligations in the age of resident duty hour restrictions.

Objectives: Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm., Materials and Methods: 634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts., Results: 5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1-16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3-28.5, P < .001)., Conclusions: This study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Objectives: Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery., Materials and Methods: Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival., Results: Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years., Conclusions: Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with oropharyngeal cancer who undergo transoral robotic surgery (TORS) and have high-risk features generally receive adjuvant chemoradiotherapy or trimodality therapy (TMT). The notion that TMT leads to high toxicity is largely based on studies that included human papilloma virus (HPV)-negative cancers and/or nonrobotic surgery; we sought to describe outcomes in HPV-associated oropharyngeal squamous cell cancer (HPV + OPSCC) undergoing TORS-TMT., Methods: In consecutive patients with HPV + OPSCC receiving TMT at an academic center from 2010 to 2017, survival was estimated using Kaplan-Meier methodology, and toxicities were ascertained via chart review., Results: In our cohort of 178 patients, 5-year survival was 93.6%. Feeding tube rates were 25.8% at therapy completion and 0.7% at 1 year. Rates of grade ≥ 3 kidney injury, anemia, and neutropenia in cisplatin-treated patients were 2.7%, 3.4%, and 11.0%, respectively., Conclusions: Patients with HPV + OPSCC who underwent TORS-TMT had excellent survival and low rates of toxicity and feeding tube dependence. These outcomes compare favorably to historical cohorts treated with definitive chemoradiotherapy., (© 2021 Wiley Periodicals LLC.)

Background: Oropharyngeal squamous cell carcinoma (OPSCC) has now surpassed cervical cancer as the most common site of HPV-related cancer in the United States. HPV-positive OPSCCs behave differently from HPV-negative tumors and often present with early lymph node involvement. The bacterial microbiome of HPV-associated OPSCC may contribute to carcinogenesis, and certain bacteria may influence the spread of cancer from the primary site to regional lymphatics., Objective: To determine the bacterial microbiome in patients with HPV-associated, early tonsil SCC and compare them to benign tonsil specimens., Method: The microbiome of primary tumor specimens and lymph nodes was compared to benign tonsillectomy specimens with pan-pathogen microarray (PathoChip)., Results: A total of 114 patients were enrolled in the study. Patients with OPSCC had a microbiome that shifted towards more gram-negative. Numerous signatures of bacterial family and species were associated with the primary tumors and lymph nodes of cancer patients, including the urogenital pathogens Proteus mirabilis and Chlamydia trachomatis, Neisseria gonorrhoeae, Shigella dysenteriae, and Orientia tsutsugamushi., Conclusion: Our results suggest that detection of urogenital pathogens is associated with lymph node metastasis for patients with HPV-positive OPSCCs. Additional studies are necessary to determine the effects of the OPSCC microbiome on disease progression and clinical outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS)., Methods: Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared., Results: The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged., Conclusions: Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates., (© 2020 Wiley Periodicals LLC.)

Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16 INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development., (© 2020 UICC.)

Introduction: The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has altered the health care environment for the management of head and neck cancers. The purpose of these guidelines is to provide direction during the pandemic for rational Head and Neck Cancer management in order to achieve a medically and ethically appropriate balance of risks and benefits., Methods: Creation of consensus document., Results: The process yielded a consensus statement among a wide range of practitioners involved in the management of patients with head and neck cancer in a multihospital tertiary care health system., Conclusions: These guidelines support an ethical approach for the management of head and neck cancers during the COVID-19 epidemic consistent with both the local standard of care as well as the head and neck oncological literature., (© 2020 Wiley Periodicals, Inc.)

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Objective: In patients with head and neck carcinoma of unknown primary (HNCUP;pT0) following TORS-assisted workup, we have adopted a pharyngeal-sparing radiation therapy (PSRT) approach targeting only the at-risk neck and omitting treatment of the pharynx. We report outcomes following PSRT, and compare to institutional historical control subjects who received pharyngeal-targeted RT (PRT)., Methods: Between 2009 and 2018, 172 patients underwent TORS-assisted endoscopy as part of their workup for HNCUP. Following TORS, 54 patients had pT0 disease, of which 45 received RT. Forty-nine percent received PSRT and 51% received PRT., Results: No statistically significant differences existed between the PSRT and PRT groups with respect to overall nodal distribution, p16 positivity (55% vs. 43%, P = .12), neck dissection rates (77% vs. 65%, P = .51), and administration of chemotherapy (55% vs. 65%, P = .55). Median follow-up for PSRT and PRT groups were 24 and 28 months, respectively (P = .04). Two-year RFS was 86% and 74% for PSRT and PRT patients, respectively (log-rank P = .30). Three and six patients recurred after PSRT and PRT, respectively. Two-year OS for PSRT and PRT patients was 91% and 74%, respectively (log-rank P = .31). Compared to PRT, PSRT was associated with statistically significantly less: grade 2+ mucositis (18% vs. 91%, P < .01), new opioid requirement (27% vs. 91%, P < .01), mean weight loss during RT (6.2 lbs vs. 17.4 lbs, P < .01), feeding tube placement during RT (5% vs. 43%, P < .01), and treatment-related unplanned hospitalizations (9% vs. 39%, P = .04)., Conclusion: Following TORS-assisted management of patients with pT0 HNCUP, we observed reduced toxicity following PSRT compared to PRT without apparent compromise of disease cure., Level of Evidence: Level 3 evidence, retrospective review comparing cases and controls Laryngoscope, 130:691-697, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Clinical responses with programmed death (PD-1) receptor-directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition., Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16 + HNSCCa received MEDI0457., Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3-5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/10 6 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8 + T cells was observed. MEDI0457 shifted the CD8 + /FoxP3 + ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin + immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1 + CD8 + T cells that were not found prior to MEDI0547 (0% vs. 1.8%)., Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes., (©2018 American Association for Cancer Research.)

Background: We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (S t O 2 ) and blood volume (tHb) were studied for associations with patient outcomes., Methods: PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion S t O 2 and tHb was measured., Results: Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but S t O 2 was higher in patients with CR. In tongue/FOM lesions, baseline S t O 2 [mean(SE)] was 54(4)% in patients (n=12) with CR versus 23(8)% in patients (n=6) with local recurrence/persistence (p=0.01). Similarly, for intact disease, baseline S t O 2 was 54(3)% in patients (n=10) with CR versus 28(8)% in patients (n=5) without CR (p=0.03). In patients with intact disease, higher baseline S t O 2 associated with 24-month local control (p=0.02)., Conclusions: Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives/hypothesis: Delineate factors impacting the creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs)., Study Design: Laboratory-based translational study., Methods: Fifty-one surgically resected HNSCCs, including 31 HPV + cancers, were implanted into NOD/SCID/IL-2Rγ -/- (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV + PDXs were analyzed in comparison to their tumors of origin., Results: Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV + HNSCC cases that failed to engraft. Successfully established HPV + PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV + nodal metastases. They also maintained elevated p16 INK4A levels and expression of E6/E7 viral oncogene transcripts., Conclusion: Reduced engraftment by HPV + tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV + lymphomas in NSG mice further reduces the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the retention of distinctive pathologic traits and viral oncogene expression by HPV + PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models., Level of Evidence: NA. Laryngoscope, 127:2777-2783, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The anterolateral thigh (ALT) free flap is one of the most commonly used donor sites in head and neck reconstruction, however, it is not typically considered when an osseous component is needed., Methods: Soft tissue harvests, cadaveric study, and retrospective analysis of a series of 10 patients undergoing angiography were performed to assess vascular supply to the femoral cortex. In 6 patients, corticocancellous split-femur was incorporated into the ALT to reconstruct bony defects of the head and neck., Results: There is a consistent blood supply to the femur from the lateral femoral circumflex artery both intraoperatively and on angiography. No fractures or orthopedic injuries have been seen to date. None of the patients had complications of bone harvest, such as deep vein thrombosis or pulmonary embolism., Conclusion: The ALT osteomyocutaneous (ALTO) flap has consistent vascular anatomy to the femoral cortex. This flap provides additional corticocancellous bone and overlying vastus intermedius muscle for the reconstruction of complex craniofacial defects. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1788-1793, 2016., (© 2016 Wiley Periodicals, Inc.)

The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B(high) fraction of cells with stem cell-like function. JARID1B(high) cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B(high) cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1B(high) cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538-49. ©2016 AACR., Competing Interests: All authors declare no conflict of interest related to this work., (©2016 American Association for Cancer Research.)

Background: The inclusion of level I in neck dissections for oropharyngeal carcinoma remains controversial. Our objectives were to evaluate the feasibility and relevance of substation node counts in level I of the neck dissection and to determine the specific substation location of metastases in level I in oropharyngeal carcinoma., Methods: Sixty specimens were retrospectively analyzed after an orientation using a new paradigm of demarcating level I specimens into 8 substations., Results: Three of the specimens (5%) in this study showed nodal metastasis in level I, one each in 3 different substations. All positive nodes in level I were associated with N+ disease in level II with 2 being radiographically occult (3.3%). Average total node count for level I was 8.1 (range, 2-19)., Conclusion: In oropharyngeal carcinoma, substation level I node quantification is feasible and relevant. This study shows a 5% risk to level I with metastasis in 3 different substations. © 2016 Wiley Periodicals, Inc. Head Neck 38:1194-1200, 2016., (© 2016 Wiley Periodicals, Inc.)

Objectives: Management of early superficial lesions in the head and neck remains complex. We performed a phase 1 trial for high-grade premalignant and early superficial lesions of the head and neck using photodynamic therapy (PDT) with Levulan (ALA)., Materials and Methods: Thirty-five subjects with high grade dysplasia, carcinoma in situ, or microinvasive (⩽1.5mm depth) squamous cell carcinoma were enrolled. Cohorts of 3-6 patients were given escalating intraoperative light doses of 50-200J/cm(2) 4-6h after oral administration of 60mg/kg ALA. Light at 629-635nm was delivered in a continuous (unfractionated) or fractionated (two-part) schema., Results: PDT was delivered to 30/35 subjects, with 29 evaluable. There was one death possibly due to the treatment. The regimen was otherwise tolerable, with a 52% rate of grade 3 mucositis which healed within several weeks. Other toxicities were generally grade 1 or 2, including odynophagia (one grade 4), voice alteration (one grade 3), and photosensitivity reactions. One patient developed grade 5 sepsis. With a median follow-up of 42months, 10 patients (34%) developed local recurrence; 4 of these received 50J/cm(2) and two each received 100, 150, and 200J/cm(2). Ten (34%) patients developed recurrence adjacent to the treated field. There was a 69% complete response rate at 3months., Conclusions: ALA-PDT is well tolerated. Maximum Tolerated Dose appears to be higher than the highest dose used in this study. Longer followup is required to analyze effect of light dose on local recurrence. High marginal recurrence rates suggest use of larger treatment fields., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Perineural invasion (PNI) is widely regarded as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Treatment guidelines recommend adjuvant radiotherapy (RT) for patients with adverse pathologic features, including PNI. The purpose of this study was to systematically review the literature to determine if patients with PNI as their only indication for adjuvant therapy benefit from adjuvant RT. In total, 339 abstracts were reviewed for relevance leaving 85 articles, which were evaluated in detail. Thirteen retrospective studies addressed the role of adjuvant RT for patients with PNI. Evidence is lacking to recommend adjuvant RT for all patients with HNSCC with PNI. However, the literature suggests that large nerve or multifocal PNI may predict worse outcome and may be a more appropriate indication for adjuvant therapy. We advocate that patients decide whether to undergo adjuvant therapy after a discussion of the limitations of current evidence. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2350-E2357, 2016., (© 2015 Wiley Periodicals, Inc.)

Objective: To characterize the clinicopathologic features of metastatic carcinomas at percutaneous endoscopic gastrostomy (PEG) tube sites., Methods: We reviewed the metastatic malignancies at PEG tube sites (2002-2011)., Results: Five patients were identified, each with primary head and neck keratinizing squamous cell carcinoma. The metastases had a mean size of 6.08 cm (95% confidence interval [CI], 3.75-8.41). The time from PEG tube placement to metastasis diagnosis was 9.8 months (95% CI, 6.59-13.01). The survival times from PEG tube placement and from metastasis diagnosis were 23.5 (95% CI, 7.65-39.35) and 13.7 (95% CI, 0-31.08) months, respectively. Compared with a meta-analysis of the largest case series, our male patients were significantly older (mean, 73 years; 95% CI, 62.2-83.9 vs mean 59 years, 95% CI, 56.0-62.0) but had similar survival times., Conclusions: Despite their older ages, our male patients had similar survival times to those reported previously. Larger series are needed to confirm our findings and explore the causes.

The evolution of oncologic surgical technology has moved toward reducing patient morbidity and mortality without compromising oncologic resection or oncologic outcomes. The goals in treating head and neck cancer are to cure patients, as well as to provide quality of life by improving functional and social outcomes through organ-preservation therapies, which may include surgery, chemotherapy, and/or radiation therapy. Transoral robotic surgery (TORS) is an emerging technique that provides several benefits over existing treatment regimens and over open surgery for head and neck cancer, including reductions in operative times, blood loss, intensive care unit stays, and overall duration of patient hospitalization. Transoral robotic techniques allow wide-view, high-resolution, magnified three-dimensional optics for visualization of the mucosal surfaces of the head and neck through an endoscope, while avoiding the extensive external cervical incisions often required for open surgeries. Radiologists play an important role in the successful outcome of these procedures, both before and after TORS. Determining a cancer patient's surgical candidacy for TORS requires a thorough preoperative radiologic evaluation, coupled with clinical and intraoperative assessment. Radiologists must pay particular attention to important anatomic landmarks that are clinical blind spots for surgeons. Knowledge of the expected postoperative imaging appearances, so that they can be distinguished from recurrent disease and second primary tumors, is essential for all radiologists involved in the care of these patients.

The number of diagnostic positron emission tomography/computed tomography (PET/CT) procedures performed in the USA and worldwide is rapidly increasing. Although the benefits of these procedures are obvious, the increasing use of radiopharmaceuticals requires a better understanding of potential adverse affects and their proper management. We present herein the first report of an allergic reaction to fluorodeoxyglucose in the setting of repeated PET/CT scans for restaging purposes in a patient with pyriform sinus cancer.

Objectives/hypothesis: To determine the prognostic influence of p16(INK4a) immunohistochemistry on the survival of resectable oropharyngeal carcinomas (OPSCC)., Study Design: Retrospective pathologic evaluation of a prospective single-arm cohort study at a tertiary referral center., Methods: There were 48 patients with resectable OPSCC who consented for transoral robotic surgery (TORS) and banked tissue specimen for assessment. TORS was with or without adjuvant radiation or chemoradiation. Main outcome measures were p16(INK4a) status, human papillomavirus status, local-regional disease control, and overall, disease-specific, and disease-free survival., Results: p16(INK4a) and HPV positivity were identified in 73% and 74% of patients respectively. With a median follow-up of 38.8 months (2.5-63.3 months), only one local-regional relapse has occurred in both the p16(INK4a)-positive and p16(INK4a) -negative cohorts. No disease-specific, disease-free, and overall survival differences were observed between p16(INK4a) -positive and p16(INK4a)-negative patients (P = .446, P = .277, P = .643, respectively)., Conclusions: p16(INK4a) was not prognostic in resectable OPSCC when treated with an initial TORS approach., (Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objectives/hypothesis: Our objective was to determine the safety, feasibility, and the adequacy of surgical margins for transoral robotic surgery (TORS), by reviewing the early results from independent institutional review board-approved clinical trials in three separate institutions., Study Design: Pooled Data from Independent Prospective Clinical Trials., Methods: One hundred ninety-two patients were initially screened, but inadequate exposure did not permit TORS in 13 (6.7%). For two additional patients, TORS was begun but intraoperatively converted to an open procedure. Thus, the intent-to-treat population was 177 patients (average age, 59 years; 81% male), predominantly comprised of tumors arising in the oropharynx (139, 78%) and larynx (26, 15%). TORS was performed for 161 (91%) patients with malignant disease: 153 (95%) with squamous cell carcinoma (T1 [50, 32.7%], T2 [74, 48.4%], T3 [21, 13.7%], T4 [8, 5.2%]), six patients (3.72%) with salivary gland tumors, and two patients with carcinoma in situ. The average follow-up was 345 days., Results: There was no intraoperative mortality or death in the immediate postoperative period. Average estimated blood loss was 83 mL; no patient required transfusion. The rate of positive margins was 4.3%. Twenty-nine patients (16%) experienced 34 serious adverse events that required hospitalization or intervention (grade 3) or were considered life threatening (grade 4, 2.3%). Tracheostomy was performed in 12.4% of all patients (22/177), but only 2.3% had a tracheostomy at last follow-up. For all patients undergoing TORS without previous therapy, the percutaneous endoscopic gastrostomy dependency rate was 5.0%. The average hospital stay was 4.2 days., Conclusions: Based on this multicenter study, TORS appears to be safe, feasible, and as such play an important role in the multidisciplinary management of head and neck cancer., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

The toxicity associated with concomitant chemoradiation for the management of laryngeal and pharyngeal carcinoma has been well documented. Minimally invasive surgical techniques offer the potential to extirpate the malignancy as a single-modality therapy and provide essential information that may direct subsequent treatment. In selected patients, radiation doses may be reduced and systemic chemotherapy may be withheld after tumor extirpation. Transoral laser microsurgery has proven effective, although inability to manipulate and suture tissue by this modality limits ablation and reconstruction of extensive defects. Transoral robotic surgery is a relatively new technique that provides several unique advantages, which include a 3-dimensional magnified view, ability to see and work around curves or angles, and the availability of 2 or 3 robotic arms that can be used to reconstruct extensive defects using either local, regional, or free flaps. Preliminary data suggest that transoral robotic surgery may provide a technique for ablation and reconstruction of pharyngeal defects that may be superior to other transoral techniques. It may also provide a means for personalizing therapy for oropharyngeal and supraglottic carcinoma., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: The aim of this study was to assess the quality of life of patients with oropharyngeal squamous cell carcinoma after transoral robotic surgery (TORS)., Methods: Short Form (SF)-8 and Performance Status Scale (PSS) questionnaires were completed prior to surgery, 6 and 12 months of follow-up., Results: In all, 38 patients treated with TORS followed by adjuvant therapy as indicated were prospectively enrolled. For PSS Eating and Diet domains, significant decreases occurred at 6 months (p ≤ .001 and p ≤ .001, respectively) but not at 12 months. Significant declines in PSS Speech were seen at 6 and 12 months (p ≤ .001 and p ≤ .001). There were no significant declines in the SF-8 domains, except for Bodily Pain and Global Health (6 months). Significantly higher PSS Eating and Diet scores were seen at 6 months for TORS alone compared with TORS and chemoradiation., Conclusions: Combination TORS and adjuvant therapy caused a temporary decrease in several domains at 6 months, returning to baseline including swallowing function in all patients., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: This retrospective study evaluated the efficacy of gabapentin for the treatment of pain syndromes related to radiation-induced mucositis in patients with head and neck cancers treated with concurrent chemoradiation., Methods: Data from 42 patients with head and neck malignancies treated with concurrent chemoradiotherapy using an intensity-modulated radiotherapy technique were analyzed. Gabapentin was initiated in the second week of radiotherapy. Opiates were prescribed in addition to gabapentin as clinically indicated to obtain adequate pain control., Results: At a median dose of 2700 mg/day of gabapentin, only 33% and 55% of patients required additional low-dose narcotic medications for pain control during the third and fourth week of treatment, respectively, despite exhibiting a grade 2 or higher mucositis in 71% and 86% of the patients, respectively. Furthermore, during the last weeks of treatment, 71% of the patients required additional low-dose opiates for adequate pain control, despite the presence of grade 2 or higher mucositis in 95% and 100% of patients at Weeks 5 and 6, respectively. Only 1 patient had a treatment-related interruption of >3 days during chemoradiotherapy., Conclusions: Gabapentin appears to be promising in reducing the need for high total doses of opioids and avoiding unplanned treatment interruptions for patients with head and neck malignancies treated with concurrent chemoradiotherapy and should be further evaluated prospectively in controlled clinical trials.

Background: This retrospective study evaluates the efficacy of gabapentin for the treatment of pain syndrome related to radiation-induced mucositis in patients with head and neck tumors., Methods: Thirty cases of head and neck malignancies treated with radiotherapy were analyzed., Results: By using a median dose of 2700 mg/day of gabapentin, only 10% of patients required additional narcotic pain medications for adequate pain relief during the third and fourth week of treatment, despite grade 2 or higher mucositis present in 56% and 73% of the patients, respectively. Likewise, during the last weeks of intensity-modulated radiation therapy (IMRT), only 35% of patients required additional narcotics for pain control, despite the presence of grade 2 or higher mucositis in 80% of cases., Conclusions: Gabapentin appears promising in reducing the need for narcotic pain medication for patients with head and neck malignancies treated with IMRT and should be further evaluated prospectively in controlled clinical trials., (Copyright 2009 Wiley Periodicals, Inc.)

Rationale and Objectives: Phosphorous magnetic resonance spectroscopy ((31)P MRS) has been used to evaluate and predict treatment response in squamous cell carcinoma of the head and neck (HNSCC). Several studies have also shown the potential of proton MRS ((1)H MRS) in assessing response in HNSCC. In view of the inherent limitations associated with performing (31)P MRS in clinical settings, the current study was performed to explore whether (1)H MRS could provide similar or complementary metabolic information in HNSCC., Materials and Methods: Fifteen patients with HNSCC underwent pretreatment magnetic resonance imaging. Both (1)H MRS and (31)P MRS were performed on viable solid parts of the metastatic lymph nodes of these patients. Peak areas of total choline (tCho) and unsuppressed water as observed on (1)H MRS and phosphomonoester (PME) and beta-nucleotide triphosphate (beta-NTP) on (31)P MRS were computed. Pearson's correlation coefficient was used to correlate the tCho/water and PME/beta-NTP ratios., Results: In all patients, the metastatic nodes appeared hyperintense on T2-weighted images and hypointense on T1-weighted images with variable signal intensity. A prominent resonance of tCho on (1)H MRS and a resonance of PME on (31)P MRS from the metastatic nodes of all patients were observed. A moderate correlation of 0.31 was observed between tCho/water and PME/beta-NTP (P > .05)., Conclusions: The biochemical pathways involved in (1)H MRS of tCho may be different from the phospholipid metabolites seen on (31)P MRS of head and neck cancers, and thus the two MRS techniques may be complementary to each other.

The Cub and Sushi Multiple Domains-1 (CSMD1) is a tumor suppressor gene on 8p23.2, where allelic loss is both frequent and associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). To understand the extent of CSMD1 aberrations in vivo, we characterized 184 primary tumors from the head and neck, lung, breast and skin for gene copy number and analyzed expression in our HNSCCs and lung squamous cell carcinomas (SCCs). We detected loss of CSMD1 in a large proportion of HNSCCs (50%), lung (46%) and breast cancers (55%), and to a lesser extent in cutaneous SCCs (29%) and basal cell carcinomas (BCCs, 17%) using array-based comparative genomic hybridization (aCGH). Studying the region more closely with quantitative real-time PCR (qPCR), the loss of CSMD1 increased to 80% in HNSCCs and 93% in lung SCCs. CSMD1 expression was decreased in tumors compared to adjacent benign tissue (65%, 13/20) and was likely due to gene loss in 45% of cases (9/20). We also identified truncated transcripts lacking exons due to DNA copy number loss (30%, 5/17) or aberrant splicing (24%, 4/17). We show loss of CSMD1 in primary HNSCC tissues, and document for the first time that CSMD1 is lost in breast, lung and cutaneous SCCs. We also show that deletions of CSMD1 and aberrant splicing contribute to altered CSMD1 function in vivo.

Purpose of Review: Head and neck surgical science has developed dramatically during the past 20 years with a major focus on organ preservation surgery. Among these organ preserving surgeries are the selective neck dissections, supracricoid partial laryngectomies, transoral laser surgeries, and now a newcomer, transoral robotic surgery utilizing the da Vinci surgical system. Transoral robotic surgery is in its infancy, but, indeed, there have been some questions raised about the role of these innovative robotic surgical techniques., Recent Findings: This article will review, point by point, the questions that have been raised concerning the feasibility; safety and efficacy; teachability; and cost effectiveness of transoral robotic surgery., Summary: Although the present literature reports early findings, without long-term oncologic outcomes, the results are consistently encouraging. Training programs have already yielded successes. Indeed, multiple institutions have shown that transoral robotic surgery programs can be successfully established yielding excellent clinical outcomes. In addition, early studies of swallowing function following transoral robotic surgery show swallowing outcomes that are superior to some of the reported chemoradiation results for equivalent lesions.

Purpose: The aim of this study was to investigate the utility of apparent diffusion coefficient (ADC) for prediction and early detection of treatment response in head and neck squamous cell carcinomas (HNSCC)., Experimental Design: Diffusion-weighted magnetic resonance imaging studies were performed on 40 patients with newly diagnosed HNSCC before, during, and after the end of chemoradiation therapy. Analysis was done on data from 33 patients after exclusion of 7 patients that had incomplete data., Results: Pretreatment ADC value of complete responders (1.04 +/- 0.19 x 10(-3) mm2/s) was significantly lower (P < 0.05) than that from partial responders (1.35 +/- 0.30 x 10(-3) mm2/s). A significant increase in ADC was observed in complete responders within 1 week of treatment (P < 0.01), which remained high until the end of the treatment. The complete responders also showed significantly higher increase in ADC than the partial responders by the first week of chemoradiation (P < 0.01). When pretreatment ADC value was used for predicting treatment response, the area under the receiver operating characteristic curve was 0.80 with a sensitivity of 65% and a specificity of 86%. However, change in ADC within the first week of chemoradiation therapy resulted in an area under the receiver operating characteristic curve of 0.88 with 86% sensitivity and 83% specificity for prediction of treatment response., Conclusions: These results suggest that ADC can be used as a marker for prediction and early detection of response to concurrent chemoradiation therapy in HNSCC.

Purpose: EF5, a 2-nitroimidazole hypoxia marker, was used to study the presence, levels, and prognostic significance of hypoxia in primary head and neck squamous cell tumors., Methods and Materials: Twenty-two patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, or larynx with at least 2 years of clinical follow-up were included in this study. Quantitative analyses of EF5 immunofluorescence was carried out, and these data were compared with patient outcome., Results: EF5 immunostaining showed substantial intra- and intertumoral hypoxic heterogeneity. The majority of cells in all tumors were well oxygenated. Three patterns of EF5 binding in cells were identified using criteria based on the cellular region that was stained (peripheral or central) and the relationship of binding to necrosis. We tested the association between EF5-binding levels with event-free and overall survival irrespective of the pattern of cellular binding or treatment regimen. Patients with tumors containing EF5-binding regions corresponding to severe hypoxia (< or =0.1% oxygen) had a shorter event-free survival time than patients with pO(2) values greater than 0.1% (p = 0.032). Nodal status was also predictive for outcome., Conclusions: These data illustrate the potential utility of EF5 binding based on quantitative immunohistochemistry of tissue pO(2) and provide support for the development of noninvasive hypoxia positron emission tomographic studies with fluorine 18-labeled EF5.

Objective: Observations indicate that the acute toxicity of chemoradiation for squamous cell carcinoma (SCC) of the head and neck is not the same as that which occurs with radiation therapy alone. Thus, the specific aim of this pilot study was to estimate the reliability and validity of a modified version of a symptom distress scale used to assess the qualitative difference in symptom distress between the 2 populations., Methods: Over a period of 4 months a consecutive sample of 56 patients with head and neck cancer were recruited from the Department of Radiation Oncology to take part in our pilot study. The Cancer Disease and Treatment Concern Scale (CDTCS) was modified by adding 15 additional items and called the Head and Neck Distress Scale (HNDS). All dimensions were interrogated with at least four questions and a domain score was generated. In addition, the Head and Neck Radiotherapy Questionnaire (HNRQ), an established 22-item multidimensional questionnaire was also administered by interview after completion of the HNDS., Results: Fifty-six patients, 32 chemoradiation patients (mean age 64 years) completed the HNDS, taking 8 to 10 minutes to complete. The HNDS scores correlated well with the HNRQ scores (r = 0.835), demonstrating an acceptable level of content and concurrent validity. There was a significant difference in the overall HNDS scores between the chemoradiation group and the radiation therapy group (ANOVA, P = 0.001)., Conclusion: The HNDS is a valid measure of acute symptom distress and appears able to discriminate between the chemoradiation and radiation alone patients. There is considerable variation in symptoms that cause these patients distress.

Objectives: The elective dissection of cervical lymph nodes from patients with early oral tongue cancer and a clinically negative neck (T1/T2N0), remains an unsettled issue that continues to be investigated. This study examines clinical and histopathologic factors through univariate and multivariate analysis to correlate the risk of neck micrometastasis in patients with T1/T2N0 squamous cell carcinoma of the oral tongue., Study Design and Methods: The clinical files and histologic sections of tumor from 45 clinically determined N0 patients were retrospectively analyzed. The factors examined include degree of tumor cell differentiation, T1/T2 staging, presence of perineural invasion, presence of angiolymphatic invasion, type of invasion front, depth of muscle invasion, and tumor thickness., Results: Independent correlates of positive occult neck metastasis included greater tumor thickness ( P = 0.01), greater depth of muscle invasion ( P = 0.01), T2 stage ( P = 0.01), poorly differentiated tumors ( P = 0.007), infiltrating-type invasion front ( P = 0.03), presence of perineural invasion ( P = 0.001), and presence of angiolymphatic invasion ( P = 0.005). The final multivariate model for estimation of an increased probability of occult neck disease included greater tumor thickness, presence of perineural invasion, infiltrating-type invasion front, poorly differentiated tumors, and T2 stage., Conclusions: The clinical and histopathologic factors studied herein permit greater selectivity and more informed decision-making than does presurgical evaluation, when addressing elective neck treatment for early N0 oral tongue cancer. The multivariate model derived from this study appears to be a more reliable method for determining the patients most likely to benefit from elective neck dissection.

Purpose: Salvage surgery alone after radiotherapy (RT) failure for locally advanced head-and-neck cancer is frequently unsuccessful because of subsequent recurrence. We designed a prospective protocol to determine the feasibility, toxicity, and preliminary efficacy of a regimen of postoperative reirradiation, chemotherapy and the radioprotector amifostine after salvage head-and-neck surgery., Methods and Materials: Eligible patients had biopsy-proven locally advanced, but resectable, recurrence without distant metastases >6 months after previous RT. After adequate healing from surgery, patients underwent RT to 54-66 Gy within 5-5.5 weeks to the resection bed (lifetime RT dose, 100-130 Gy). The fractionation was 1.5 Gy b.i.d. within 2 weeks, followed by a 1-week break, followed by 1.5 Gy b.i.d. to a total of 54-66 Gy. Chemotherapy consisted of cisplatin 25 mg/m(2)/d three times and 5-fluorouracil 500 mg/m(2)/d continuous infusion for 4 days, for two cycles (Weeks 1 and 5). Amifostine (500 mg i.v.) was administered daily, 30 min before either the morning or the afternoon RT., Results: Between 1998 and 2001, 16 patients were enrolled and studied. Two patients had gross residual disease after surgery; all other patients underwent complete surgical resection but had high-risk features (rT3-T4 and/or N+ disease). Three patients (19%) had serious acute toxicity events (nonneutropenic infections) that were reversible. The median follow-up was 35 months. The actuarial locoregional control rate was 81% at 3 years. Three patients developed isolated distant metastases and one developed a fatal second primary cancer (hepatoma). The 2- and 3-year actuarial event-free survival rate was 81% and 50%, respectively. The 2- and 3-year actuarial overall survival rate was 81% and 63%, respectively. Both patients who had gross residual disease after surgery had early recurrence; if these patients were excluded from analysis, the 3-year actuarial survival and event-free survival rate was 67% and 59%, respectively. Of the 16 patients, 6 (38%) developed Grade 3+ late toxicity, including one fatal stroke and two life-threatening major vessel necrosis and/or bleeding events., Conclusion: This regimen of postoperative reirradiation/chemotherapy plus amifostine is feasible and was well tolerated acutely, with encouraging oncologic efficacy. However, the incidence and severity of late effects was significant and suggests that modifications are necessary for future studies in this patient population.

Background: Allogeneic transfusions are necessary in 14% to 80% of patients undergoing major head and neck cancer surgery. Defining the risk for receiving allogeneic transfusion allows for informed decisions regarding appropriateness of type and crossmatch, preoperative autologous blood donation, and priming with erythropoietin. Based on logistic regression analysis of transfusion risk factors in 438 patients, we developed a transfusion prediction risk assessment (TPRA) model to determine the need for transfusion based on the preoperative hemoglobin value, tumor stage, and need for flap reconstruction., Objective: To examine the utility of this TPRA model in clinical practice by assessing the performance of the model in a validation set of patients., Methods: Between 1996 and 1999, 125 consecutive patients entered into a clinical care pathway underwent major surgical procedures. The ability of the model to discriminate between patients requiring and those not requiring transfusion was assessed using the area under the receiver operating characteristic curve. The agreement between actual and predicted risks was tested using the chi2 goodness-of-fit statistic., Results: The overall transfusion rate was 25%. A 1-U transfusion was required in 7 patients, and multiple units were necessary for 24 patients. Flap reconstruction was required in 63 patients, 44 patients had preoperative anemia by normative values, and 64 had T3/T4 tumors. Among the low-risk non-T3/T4 patients whose preoperative hemoglobin level was normal, the actual/predicted transfusion rate without flap reconstruction was 10%/2%. For high-risk patients with T3/T4 tumors, anemia, and flap reconstruction, the actual/predicted transfusion rate was 43%/65%. The area under the receiver operating characteristic curve was 0.72. The goodness-of-fit statistic indicated lack of fit of the original model, but a recalibrated model fit the observed data well., Conclusions: In general, the TPRA model identifies patients at low or high risk for allogeneic transfusion and provides guidelines for preoperative counseling regarding the risk of receiving a transfusion. Knowledge of a patient's risk can help direct cost-effective utilization of type and crossmatch, preoperative autologous blood donation, and preoperative priming with erythropoietin.

Objective: To determine the rate of cerebrovascular events (stroke) in patients irradiated to high doses for squamous cell carcinoma of the head and neck., Study Design: Retrospective chart review of 413 patients treated from 1987 to 2000 with squamous cell carcinoma of the head and neck was performed to determine the risk of stroke compared with the expected rate., Methods: Surgical, radiotherapeutic, radiological, and clinical or office records of 413 patients were analyzed, and data were collected regarding clinical risk factors for stroke, irradiation parameters, and follow-up on whether or not a stroke event occurred. The actuarial risk of stroke for this population was calculated and compared with expected risk from population-based data., Results: Of the 413 patients, 20 had strokes in follow-up, occurring between 2 and 146 months after radiotherapy. The 5-year actuarial rate of stroke was 12%, which corresponded to a relative risk of 2.09 ( P=.0007) compared with the population-based "expected" data. Median radiation therapy dose was 64 Gy; there was no correlation between radiation therapy dose and stroke risk. No correlation was identified between surgery near the carotids and stroke risk., Conclusions: An association between high-dose cervical irradiation for squamous cell carcinoma of the head and neck and stroke is demonstrated. Although the relative risk is approximately doubled, the absolute risk is modest in comparison to the risk of cancer recurrence. Further study of this association and possible interventions is warranted.

Objectives: To describe the design and impact of 3 intraoperative pathways for the treatment of head and neck cancers; to detail the pathways schematically to illustrate projected intraoperative flow and teamwork; and to analyze impact on procedure and case lengths in each pathway and in comparison with historical prepathway average times., Setting: Tertiary-level academic health system main operating room., Patients: Twenty-one patients undergoing transcervical (TC) resection (n = 11), transmandibular (TM) resection (n = 8), or laryngopharyngectomy (LP) (n = 2) with radial forearm free-flap reconstruction for ablative or reconstructive reasons were pathway eligible. A convenience sample of 16 patients undergoing TC resection, 7 undergoing TM resection, and 7 undergoing LP prepathway is used for comparison., Intervention: Our academic medical center uses 3 intraoperative clinical pathways to manage resource use and streamline care for patients. These 3 pathways were designed schematically by an interdisciplinary team. The pathways plan progression of the case by timed actions for surgical, anesthesia, and nursing teams., Main Outcome Measures: Procedure and case lengths., Results: The TC pathway procedure and case length averaged 10.48 and 12.33 hours, respectively; TM pathway procedure and case lengths, 11.19 and 13.32 hours, respectively; and LP pathway procedure and case lengths, 12.42 and 13.83 hours, respectively. Aggregate averages were 10.93 hours and 12.85 hours for procedure and case length, respectively. The average pathway case lengths of 12.33, 13.32, and 13.83 hours compare favorably with our target times of 13, 14, and 15 hours, respectively. Environmental management, work flow, and team satisfaction anecdotally increased postpathway., Conclusions: Intraoperative pathways afford enhanced time and action efficiency to streamline care of patients undergoing head and neck procedures. Pathway implementation produced time savings. Our results suggest that implementation of such pathways will benefit similar academic medical centers seeking to improve intraoperative resource use to improve performance in the care of patients undergoing head and neck procedures.

Background: Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC)., Methods: Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design., Results: Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m2 in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade I (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response., Conclusions: Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.

Objective: This article investigates the effect of patient age on postoperative pathway length of stay (LOS) for head and neck surgery. Aggregate clinical results for 43 patients, enrolled in the CCP from June 1996-July 1997, are described. Patient age, comorbid status, and postoperative complications are analyzed with respect to impact on LOS., Setting: Tertiary level academic medical center with an operative otorhinolaryngology volume of approximately 1200 cases per year., Patients: Forty-three patients undergoing head and neck resection with primary closure, local flap, or free flap closure were enrolled on CCP from June 1996-July 1997. Length of stay, frequency of selected aggregated comorbidities, and frequencies of complications are analyzed with nonparametric statistics. A pre-pathway group of 87 consecutive patients is used for comparison., Main Outcome Measures: Length of stay and age., Results: Median actual LOS post-pathway for the patients enrolled in the first year of the pathway was 8 days. This met the CCP target and improved on pre-pathway LOS by 5 days (p <.001). The average LOS increased 25% from 8 days to 10 days for patients older than 65 years of age (p =.036, Mann-Whitney U test). Presence of a comorbidity and a complication concomitantly was statistically associated with increased LOS though not with advancing age (p =.003)., Conclusions: The CCP-reported performance improvement achieved by this pathway suggests improved resource use, and improved patient outcomes are achieved for postoperative care of head and neck surgery patients. Our experience suggests that advancing age creates a clinically significant increase in resource use represented by our finding of increasing LOS. This finding warrants further investigation., (Copyright 2002 Wiley Periodicals, Inc.)

Background: Aggressive nonmelanoma skin cancer (ANMSC) of the head and neck may require parotidectomy because of neurotropic spread, direct invasion of the parotid gland, or parotid metastasis., Objective: To review our experience with parotidectomy in the treatment of these tumors to examine the indications for this procedure and to analyze treatment outcomes. We emphasize the importance of early identification of an ANMSC and a systematic approach to treatment., Design: Review of 23 patients with an ANMSC who required parotidectomy with or without facial (VII) nerve sacrifice between January 5, 1996, and December 27, 1999. Median follow-up for all patients was 24 months., Setting: Academic tertiary care referral center., Patients: This study focused on 23 (median age, 71 years) of 54 patients treated for an ANMSC. Most tumors were in the periauricular (n = 9) and the frontozygomatic (n = 6) areas. Seven patients presented with facial weakness or paralysis. Three patients had clinically evident parotid metastasis, while 14 patients had tumors directly invading the parotid gland. Eighteen patients had recurrent disease that had been treated previously with Mohs micrographic surgery., Interventions: Following wide local excision of the ANMSC, 12 patients had resection of the lateral parotid lobe with preservation of the nerve, while 11 required radical parotidectomy with sacrifice of 1 or more branches. Nineteen patients received cervical lymphadenectomy. Postoperative radiotherapy was administered in 19 patients., Main Outcome Measures: Tumor pathologic findings (specifically, perineural invasion of the facial nerve), locoregional control or recurrence, disease-free survival, disease-specific survival, and overall survival., Results: Neurotropic spread to the facial nerve was present in 6 patients and was more likely to occur in younger patients (51 vs 75 years, P =.006). Locoregional failures occurred in 9 patients following treatment. Patients who required parotidectomy in their surgical treatment for an ANMSC were more likely to have recurrent disease (P =.0002). Disease-specific and overall survival was 79% and 69%, respectively, at 42 months., Conclusions: Patients with ANMSC may require parotidectomy in the context of neurotropic spread, regional metastasis, or direct invasion into the parotid gland. Surgery combined with postoperative radiotherapy is necessary in most patients because of adverse clinical and pathologic findings. A systematic approach to the management of the parotid and facial nerve in the presence of these aggressive tumors is required. Despite comprehensive treatment, local recurrence of ANMSC and mortality remain high.

Objective: To evaluate the durability over time of the reduction of resource utilization after implementing a clinical care pathway (CCP) for head and neck cancer surgery., Design: Cohort study., Setting: A tertiary care academic medical center., Patients: We studied control subjects from 1995 (pre-CCP) (n = 87), a cohort from July 1, 1996, through July 31, 1997 (the first year after CCP implementation) (n = 43), and a cohort from 1999 (n = 82) after major resection and tracheostomy for upper aerodigestive tract cancer., Interventions: Starting July 1, 1996, all patients undergoing major resection for head and neck cancer were treated using a CCP, which delineates daily interventions and goals., Main Outcome Measures: Length of stay (LOS), readmission and complication rates, and hospital charges., Results: Median total LOS and LOS exclusive of the intensive care unit decreased in the first year and remained stable at 3 years (from 13.0 to 8.0 days and from 10.5 to 6.4 days, respectively). The intensive care unit LOS decreased across 3 years from 2.2 to 1.1 days (P=.001). Median total charges declined from 105,410 US dollars pre-CCP to 65,919 US dollars at 3 years. Incidence of postoperative pneumonia decreased from 12% to 1% (P=.02), and readmission rate decreased from 18% to 11% (P=.37) across 3 years., Conclusions: The CCP for head and neck cancer maintained the improvement in LOS and charges seen in the first year of implementation and continues to decrease resource utilization while enhancing quality of care.

Background: To determine the effect of treatment time-related factors on outcome in patients treated with surgery and postoperative radiation therapy (RT) for locally advanced squamous cell carcinoma of head and neck (SCCHN) METHODS: A retrospective review was performed on 208 consecutive patients treated from 1992 to 1997 with surgery and postoperative RT (> or =55 Gy) for SCCHN. The treatment time factors considered were (1) interval from surgery to the start of RT; (2) RT duration; and (3) the total time from surgery to completion of RT (treatment package time). Treatment package time was dichotomized into short (< or =100 days) vs long (>100 days) categories. Other variables considered were clinical and pathologic staging, margin status, RT dose, and tumor site. Patients were also divided into intermediate- and high-risk groups on the basis of eligibility for RTOG 95-01. Univariate (logrank) and multivariate analyses were performed., Results: Median follow-up for surviving patients was 24 months. Actuarial 2-year locoregional control (LRC) and survival rates were 82% and 71%, respectively. In univariate analysis, factors associated with higher locoregional failure were high-risk group (p =.011), margin status (p =.038), pathologic stage (p =.035), clinical N stage (p =.006), package time (p =.013), and RT treatment time (p =.03). Package time was also a significant predictor of survival in univariate analysis (p =.021). The other two individual time factors, tumor factors, and RT dose were not significant. Both risk status and treatment package time were significant factors in a multivariate model of LRC., Conclusions: A total treatment package time of <100 days is associated with improved tumor control and survival. Every effort should be made to keep the time from surgery to the completion of postoperative RT to <100 days., (Copyright 2002 John Wiley & Sons, Inc.)

Background: Allogeneic transfusions are necessary in 14% to 80% of patients undergoing major head and neck cancer surgery. Defining the risk for receiving allogeneic transfusion allows for informed decisions regarding appropriateness of type and crossmatch, preoperative autologous blood donation, and priming with erythropoietin. Based on logistic regression analysis of transfusion risk factors in 438 patients, we developed a transfusion prediction risk assessment (TPRA) model to determine the need for transfusion based on the preoperative hemoglobin value, tumor stage, and need for flap reconstruction. Objective: To examine the utility of this TPRA model in clinical practice by assessing the performance of the model in a validation set of patients. Methods: Between 1996 and 1999, 125 consecutive patients entered into a clinical care pathway underwent major surgical procedures. The ability of the model to discriminate between patients requiring and those not requiring transfusion was assessed using the area under the receiver operating characteristic curve. The agreement between actual and predicted risks was tested using the χ[sup 2] goodness-of-fit statistic. Results: The overall transfusion rate was 25%. A 1-U transfusion was required in 7 patients, and multiple units were necessary for 24 patients. Flap reconstruction was required in 63 patients, 44 patients had preoperative anemia by normative values, and 64 had T3/T4 tumors. Among the low-risk non-T3/T4 patients whose preoperative hemoglobin level was normal, the actual/predicted transfusion rate without flap reconstruction was 10%/2%. For high-risk patients with T3/T4 tumors, anemia, and flap reconstruction, the actual/predicted transfusion rate was 43%/65%. The area under the receiver operating characteristic curve was 0.72. The goodness-of-fit statistic indicated lack of fit of the original model, but a recalibrated model fit the observed data well. Conclusions: In general, the TPRA model identifies patients at low or high risk for allogeneic transfusion and provides guidelines for preoperative counseling regarding the risk of receiving a transfusion. Knowledge of a patient's risk can help direct cost-effective utilization of type and crossmatch, preoperative autologous blood donation, and preoperative priming with erythropoietin. [ABSTRACT FROM AUTHOR]